1. Technical Field
The invention relates to a new method for the preparation of the pyridobenzoxazine, 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine.
2. Background
The pyridobenzoxazine, 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine is a key intermediate in the synthesis of the fluoroquinolone antibiotic, Ofloxacin which was discovered by I. Hayakawa and Y. Tanaka, Daiichi Seiyaku Co., Ltd., U.S. Pat. No. 4,382,892, 1983. Ofloxacin is one of the leading antibacterial fluoroquinolones in the market today; e.g. see: Chem.Pharm.Bull.32 (12) 4907-4913, 4923 (1984); Daiichi Seiyaku Drugs Future 1983, 8, 395; Collect. Czech. Chem. Commun. (vol. 56), 1937, (1991). The s-(-) isomer of 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine can be utilized in the synthesis of the optically active form of Ofloxacin known as Levofloxacin. Levofloxacin is 8 to 128 times more active than Ofloxacin depending upon the bacteria tested, J. Med. Chem. 1987, 30, 2283-2286, Drugs of the Future 1992, 17(7); 559-563. Une, T.; Antimicrob. Agents Chemother. 32; 1336-1340 (1989).
Hayakawa's method of preparation of Ofloxacin is described in EP 0047005A1 and starts with 2,3,4-trifluoronitrobenzene which is converted to the 2-hydroxy-3,4-difluoronitrobenzene in dimethylsulfoxide in the presence of potassium hydroxide. The yield for this reaction is only 29%. The low yield of this step limits the overall yield of Hayakawa's process. Other patents cite the use of this material in their routes to Ofloxacin; e.g. U.S. Pat. No. 5,136,059 and EP 0333815 A2. The 2-hydroxy-3,4 difluoronitrobenzene is converted to 2-acetonyloxy-3,4-difluoronitro-benzene which is reductively ring closed to give an isomeric mixture of 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine (Formula 1). This material is converted to diethyl-(7,8-difluoro-2,3-dihydro-3-methyl 4H 1,4 benzoxazinyl) methylenemalonate by reaction with diethylethoxymethylenamalonate. Cyclization of this malonate ester in ethylpolyphosphate gives (+,-)-ethyl 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazi ne-6-carboxylate. This benzoxazine carboxylate ester is then hydrolyzed to the corresponding acid. The acid is reacted with N-methylpiperazine in dimethylsulfoxide to form Ofloxacin, 9-fluoro-10-(4-methyl-1-piperazinyl)-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[ 1,2,3-de][1,4]benzoxazine-6-carboxylic acid. The reaction sequence is shown below: ##STR1##
Another route to Ofloxacin is described in U.S. Pat. Nos. 4,762,831; 4,859,773; 4,958,045; and DE 3522406 A1. It utilizes tetrafluorobenzoic acid which is more expensive than intermediate trifluoronitrobenzene or the corresponding aniline. The process involves more steps than that of Hayakawa. Other routes to Ofloxacin are described in Chem. Pharm. Bull., 34 (10): 4098-4102 (1986). This preparation is illustrated in the following reaction scheme: ##STR2##